This invention relates to human immunodeficiency viruses in general and, more specifically to non-infectious vaccines for the treatment of human immunodeficiency disease.
AIDS is a lethal disease caused by human immunodeficiency viruses HIV-1 and HIV-2. This disease is characterized by a long, latent asymptomatic phase. During this phase the HIV particles are suppressed by the body""s immune defense system. The next phase of the disease occurs when the body""s immune system is no longer able to suppress the viral particles. At this stage of the disease, the HIV viral particles attack and destroy a key component of the body""s immune defense system called CD4+ cells. Once these cells are destroyed, the third and final phase of the disease occurs. During this last phase, the body is extremely susceptible to infections by many different kinds of diseases. These so-called secondary infections are the cause of death in many AIDS patients.
One of the central mysteries about AIDS is why HIV particles can exist in the body for so long, yet the patient remains asymptomatic. As a corollary to this riddle, there is no certain explanation why the immune system suddenly fails to be effective against the particles, thus enabling the second phase of the disease.
One theory for the sudden onslaught of the HIV particles on the CD4+ cells is that this onslaught is made by xe2x80x9cdefectivexe2x80x9d HIV particles. These new, defective particles are not recognized by the body""s immune system. These defective particles have mutations in some of the key polypeptides of an HIV viral particle, yet somehow are still able to affect sufficient damage on the CD4+ cells by means other than the classical invasion of the cells.
Surprisingly, non-infectious HIV particles produced by a cell called xe2x80x9cL-2xe2x80x9d fuse more efficiently than wild-type HIV with a subpopulation of CD4+ cells. The enhanced fusion is caused by the 4-fold increased level of gp120, the two deletion mutations in gp120, altered conformational epitopes of gp120 and/or a combination of these factors, as well as mutant forms of Nef, gp41, protease, and Vpr, as discussed below. The fusion is far from the typical action of normal HIV infectious viral particles, in that it leads to the stimulation and release of II-2R, Fas ligand and interferon-gamma 1 from a small subset of CD4+ cells (Kameoka et al., International Immunology 9(10):1453-1462 (1997)). This occurs after L-2 particle fusion with these CD4+ cells, a high percentage of uninfected, healthy neighboring CD4+, as well as CD8+ cells, are prematurely thrown into a programmed cell death cycle, ultimately resulting in apoptosis. Apoptosis is a natural process in most cells in the body, but only after such cells have become senescent. Fusion of L-2 particles with CD4+ cells can also cause such cells to form multinucleated protoplasmic masses called xe2x80x9csyncytiaxe2x80x9d, which die shortly thereafter.
Thus, there exists a need to detect such defective HIV particles in the infected population; both for asymptomatic carriers, as well as for ARC (AIDS elated Complex) or AIDS patients. Furthermore, a need exists for prophylactic, immunogenic, and therapeutic agents for such defective particles, as well as polypeptides or fragments of polypeptides derived from the particles or their mutant nucleic acid sequences. This need exists due to the fact that mutations found in L-2 particles are normally produced in HIV infected individuals, so that development of immunity to them by natural or artificial means is a key to thwarting the pathogenic process leading to ARC and AIDS. This invention provides these advantages and more.